ERC FUNDED PROJECTS

ProjectNeural mechanisms of body ownership and the projection of ownership onto artificial bodies

Researcher (PI)H. Henrik Ehrsson

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsStarting Grant (StG), LS4, ERC-2007-StG

SummaryHow do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

How do we recognize that our limbs are part of our own body, and why do we feel that one’s self is located inside the body? These fundamental questions have been discussed in theology, philosophy and psychology for millennia. The aim of my ground-breaking research programme is to identify the neuronal mechanisms that produce the sense of ownership of the body, and the processes responsible for the feeling that the self is located inside the physical body. To solve these questions I will adopt an inter-disciplinary approach using state-of-the-art methods from the fields of imaging neuroscience, experimental psychology, computer science and robotics. My first hypothesis is that the mechanism for body ownership is the integration of information from different sensory modalities (vision, touch and muscle sense) in multi-sensory brain areas (ventral premotor and intraparietal cortex). My second hypothesis is that the sense of where you are located in the environment is mediated by allocentric spatial representations in medial temporal lobes. To test this, I will use perceptual illusions and virtual-reality techniques that allow me to manipulate body ownership and the perceived location of the self, in conjunction with non-invasive recordings of brain activity in healthy humans. Functional magnetic resonance imaging and electroencephalography will be used to identify the neuronal correlates of ownership and ‘in-body experiences’, while transcranial magnetic stimulation will be used to examine the causal relationship between neural activity and ownership. It is no overstatement to say that my pioneering work could define a new sub-field in cognitive neuroscience dealing with how the brain represents the self. These basic scientific discoveries will be used in new frontier applications. For example, the development of a prosthetic limb that feels just like a real limb, and a method of controlling humanoid robots by the illusion of ‘becoming the robot’.

Max ERC Funding

909 850 €

Duration

Start date: 2008-12-01, End date: 2013-11-30

Project acronymCAAXPROCESSINGHUMDIS

ProjectCAAX Protein Processing in Human DIsease: From Cancer to Progeria

Researcher (PI)Martin Olof Bergö

Host Institution (HI)GOETEBORGS UNIVERSITET

Call DetailsStarting Grant (StG), LS6, ERC-2007-StG

SummaryMy objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

Max ERC Funding

1 689 600 €

Duration

Start date: 2008-06-01, End date: 2013-05-31

Project acronymDII

ProjectThe Design of International Institutions: Legitimacy, Effectiveness and Distribution in Global Governance

Researcher (PI)Jonas Tallberg

Host Institution (HI)STOCKHOLMS UNIVERSITET

Call DetailsStarting Grant (StG), SH2, ERC-2007-StG

SummaryOne of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.

One of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.

SummaryThe long-term goal of our research is to advance the state-of-the-art in molecular simulation algorithms by 4-5 orders of magnitude, particularly in the context of the GROMACS software we are developing. This is an immense challenge, but with huge potential rewards: it will be an amazing virtual microscope for basic chemistry, polymer and material science research; it could help us understand the molecular basis of diseases such as Creutzfeldt-Jacob, and it would enable rational design rather than random screening for future drugs. To realize it, we will focus on four critical topics: • ALGORITHMS FOR SIMULATION ON GRAPHICS AND OTHER STREAMING PROCESSORS: Graphics cards and the test Intel 80-core chip are not only the most powerful processors available, but this type of streaming architectures will power many supercomputers in 3-5 years, and it is thus critical that we design new “streamable” MD algorithms. • MULTISCALE MODELING: We will develop virtual-site-based methods to bridge atomic and mesoscopic dynamics, QM/MM, and mixed explicit/implicit solvent models with water layers around macromolecules. • MULTI-LEVEL PARALLEL & DISTRIBUTED SIMULATION: Distributed computing provides virtually infinite computer power, but has been limited to small systems. We will address this by combining SMP parallelization and Markov State Models that partition phase space into transition/local dynamics to enable distributed simulation of arbitrary systems. • EFFICIENT FREE ENERGY CALCULATIONS: We will design algorithms for multi-conformational parallel sampling, implement Bennett Acceptance Ratios in Gromacs, correction terms for PME lattice sums, and combine standard force fields with polarization/multipoles, e.g. Amoeba. We have a very strong track record of converting methodological advances into applications, and the results will have impact on a wide range of fields from biomolecules and polymer science through material simulations and nanotechnology.

The long-term goal of our research is to advance the state-of-the-art in molecular simulation algorithms by 4-5 orders of magnitude, particularly in the context of the GROMACS software we are developing. This is an immense challenge, but with huge potential rewards: it will be an amazing virtual microscope for basic chemistry, polymer and material science research; it could help us understand the molecular basis of diseases such as Creutzfeldt-Jacob, and it would enable rational design rather than random screening for future drugs. To realize it, we will focus on four critical topics: • ALGORITHMS FOR SIMULATION ON GRAPHICS AND OTHER STREAMING PROCESSORS: Graphics cards and the test Intel 80-core chip are not only the most powerful processors available, but this type of streaming architectures will power many supercomputers in 3-5 years, and it is thus critical that we design new “streamable” MD algorithms. • MULTISCALE MODELING: We will develop virtual-site-based methods to bridge atomic and mesoscopic dynamics, QM/MM, and mixed explicit/implicit solvent models with water layers around macromolecules. • MULTI-LEVEL PARALLEL & DISTRIBUTED SIMULATION: Distributed computing provides virtually infinite computer power, but has been limited to small systems. We will address this by combining SMP parallelization and Markov State Models that partition phase space into transition/local dynamics to enable distributed simulation of arbitrary systems. • EFFICIENT FREE ENERGY CALCULATIONS: We will design algorithms for multi-conformational parallel sampling, implement Bennett Acceptance Ratios in Gromacs, correction terms for PME lattice sums, and combine standard force fields with polarization/multipoles, e.g. Amoeba. We have a very strong track record of converting methodological advances into applications, and the results will have impact on a wide range of fields from biomolecules and polymer science through material simulations and nanotechnology.

Max ERC Funding

992 413 €

Duration

Start date: 2008-09-01, End date: 2013-08-31

Project acronymGENOMIC STABILITY

ProjectGenomic stability -chromosome segregation and repair

Researcher (PI)Camilla Björkegren Sjögren

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsStarting Grant (StG), LS1, ERC-2007-StG

SummaryThe eukaryotic genome combines a highly dynamic nature with stable transmission of genetic information from mother to daughter cells. This is achieved by a plethora of protein networks regulating processes such as chromosome duplication, segregation and repair. The principal aim of our research is to determine the molecular interplay between chromosome segregation and repair. Accurate execution of these two events is crucial for the maintenance of genome stability, which in turn is essential for life. Additionally, erroneous segregation or repair leads to chromosomal aberrations that are linked to tumor formation and human developmental syndromes. Thus, our investigations are not only crucial in a basic research perspective, but important also for the understanding of the causes of human disease. The research is based on the budding yeast model system, and combines genome-wide analysis of protein-chromosome interactions with cell-based experimental systems. Our investigations have until now revealed that chromosome segregation and repair are directly linked through two evolutionary conserved SMC (Structural Maintenance of Chromosomes) protein complexes, Cohesin and the Smc5/6 complex. The project now further explores the molecular details of this connection, bringing light into this unexplored area of research, and deciphering the cellular defense against genomic alterations connected to cancer and developmental diseases.

The eukaryotic genome combines a highly dynamic nature with stable transmission of genetic information from mother to daughter cells. This is achieved by a plethora of protein networks regulating processes such as chromosome duplication, segregation and repair. The principal aim of our research is to determine the molecular interplay between chromosome segregation and repair. Accurate execution of these two events is crucial for the maintenance of genome stability, which in turn is essential for life. Additionally, erroneous segregation or repair leads to chromosomal aberrations that are linked to tumor formation and human developmental syndromes. Thus, our investigations are not only crucial in a basic research perspective, but important also for the understanding of the causes of human disease. The research is based on the budding yeast model system, and combines genome-wide analysis of protein-chromosome interactions with cell-based experimental systems. Our investigations have until now revealed that chromosome segregation and repair are directly linked through two evolutionary conserved SMC (Structural Maintenance of Chromosomes) protein complexes, Cohesin and the Smc5/6 complex. The project now further explores the molecular details of this connection, bringing light into this unexplored area of research, and deciphering the cellular defense against genomic alterations connected to cancer and developmental diseases.

SummaryComputer vision concerns itself with understanding the real world through the analysis of images. Typical problems are object recognition, medical image segmentation, geometric reconstruction problems and navigation of autonomous vehicles. Such problems often lead to complicated optimization problems with a mixture of discrete and continuous variables, or even infinite dimensional variables in terms of curves and surfaces. Today, state-of-the-art in solving these problems generally relies on heuristic methods that generate only local optima of various qualities. During the last few years, work by the applicant, co-workers, and others has opened new possibilities. This research project builds on this. We will in this project focus on developing new global optimization methods for computing high-quality solutions for a broad class of problems. A guiding principle will be to relax the original, complicated problem to an approximate, simpler one to which globally optimal solutions can more easily be computed. Technically, this relaxed problem often is convex. A crucial point in this approach is to estimate the quality of the exact solution of the approximate problem compared to the (unknown) global optimum of the original problem. Preliminary results have been well received by the research community and we now wish to extend this work to more difficult and more general problem settings, resulting in thorough re-examination of algorithms used widely in different and trans-disciplinary fields. This project is to be considered as a basic research project with relevance to industry. The expected outcome is new knowledge spread to a wide community through scientific papers published at international journals and conferences as well as publicly available software.

Computer vision concerns itself with understanding the real world through the analysis of images. Typical problems are object recognition, medical image segmentation, geometric reconstruction problems and navigation of autonomous vehicles. Such problems often lead to complicated optimization problems with a mixture of discrete and continuous variables, or even infinite dimensional variables in terms of curves and surfaces. Today, state-of-the-art in solving these problems generally relies on heuristic methods that generate only local optima of various qualities. During the last few years, work by the applicant, co-workers, and others has opened new possibilities. This research project builds on this. We will in this project focus on developing new global optimization methods for computing high-quality solutions for a broad class of problems. A guiding principle will be to relax the original, complicated problem to an approximate, simpler one to which globally optimal solutions can more easily be computed. Technically, this relaxed problem often is convex. A crucial point in this approach is to estimate the quality of the exact solution of the approximate problem compared to the (unknown) global optimum of the original problem. Preliminary results have been well received by the research community and we now wish to extend this work to more difficult and more general problem settings, resulting in thorough re-examination of algorithms used widely in different and trans-disciplinary fields. This project is to be considered as a basic research project with relevance to industry. The expected outcome is new knowledge spread to a wide community through scientific papers published at international journals and conferences as well as publicly available software.

Max ERC Funding

1 440 000 €

Duration

Start date: 2008-07-01, End date: 2013-06-30

Project acronymMEDIA AND POLICY

ProjectThe impact of mass media on public policy

Researcher (PI)David Strömberg

Host Institution (HI)STOCKHOLMS UNIVERSITET

Call DetailsStarting Grant (StG), SH1, ERC-2007-StG

SummaryThis project will study political economics issues, that is, how public policies are influenced by political considerations. The emphasis is on the mass media's role in shaping government policies. A smaller part will also analyze how different political institutions and economic outcomes influence policy and the impact of extreme weather events. The project will mainly be empirical, using statistical methods with a focus on identifying causal effects, rather than correlations. The study of media effects will analyze the political impact of having a press actively covering politics. This is an important issue, largely unanswered because the presence of an active press is endogenous to things like corruption and voter information. We will address this question in the special case of media coverage of US Congressional elections. To identify the effect of news, we will use the fact that the amount of coverage is driven to a large extent by the coincidental match between media markets and congressional districts. We intend to analyze the effect of active press coverage on, (i) voter information, (ii) politicians actions, and (iii) federal funds per capita. The project will also investigate how political institutions and economic outcomes influences the health impacts (such as mortality among old and infants) of weather extremes. Historical weather data at a very detailed geographical level will be combined with socio-economic data in a panel (longitudinal) form. This is joint work with meteorologists who will construct historical weather data at fine grids across the globe. The part dealing with structural political economics aims to develop a framework for investigating the effects of institutions on economic policy. In existing work, there is a disconnect between the theoretical modelling and empirical applications. The aim is to close this gap.

This project will study political economics issues, that is, how public policies are influenced by political considerations. The emphasis is on the mass media's role in shaping government policies. A smaller part will also analyze how different political institutions and economic outcomes influence policy and the impact of extreme weather events. The project will mainly be empirical, using statistical methods with a focus on identifying causal effects, rather than correlations. The study of media effects will analyze the political impact of having a press actively covering politics. This is an important issue, largely unanswered because the presence of an active press is endogenous to things like corruption and voter information. We will address this question in the special case of media coverage of US Congressional elections. To identify the effect of news, we will use the fact that the amount of coverage is driven to a large extent by the coincidental match between media markets and congressional districts. We intend to analyze the effect of active press coverage on, (i) voter information, (ii) politicians actions, and (iii) federal funds per capita. The project will also investigate how political institutions and economic outcomes influences the health impacts (such as mortality among old and infants) of weather extremes. Historical weather data at a very detailed geographical level will be combined with socio-economic data in a panel (longitudinal) form. This is joint work with meteorologists who will construct historical weather data at fine grids across the globe. The part dealing with structural political economics aims to develop a framework for investigating the effects of institutions on economic policy. In existing work, there is a disconnect between the theoretical modelling and empirical applications. The aim is to close this gap.

SummaryPhotochromic molecules, or photochromes, can be reversibly isomerized between two thermally stable forms by exposure to light of different wavelengths. Upon isomerization, properties such as excitation energies, redox properties, charge distribution, and structure experience significant changes. These changes can be harnessed to switch “on” or “off” the action of a variety of photophysical processes in the photochromic constructs, e.g., energy and electron transfer. Until now, the focus of my research has been to show proof of principle for a large selection of molecule-based photonically controlled logic devices (solution based) with the functional basis in the switching of the transfer processes mentioned above. Now, I wish to extend the study to include experiments in the solid state, e.g., polymer matrices. Taking the step into doing solid state chemistry is not only a prerequisite for any real-world application. It will also allow for experiments that cannot be performed in fluid solution, such as aligning molecules in a stretched film for chemistry with polarized light, and immobilization of molecules for selective addressing in a three-dimensional array of volume elements. Furthermore, I intend to investigate the possibility to photonically control the membrane penetrating and the DNA-binding abilities of photochromes, aiming at, in a long-term perspective, light-activated cancer drugs. Due to the fact that both the structure and the charge distribution of a photochrome may change drastically upon isomerization, one of the two isomeric forms is often suitable for penetrating a membrane. Inside the membrane, e.g., in a cell, the photochrome can be photo-isomerized to a structure with high affinity for strong binding to DNA. Upon binding, transcription is inhibited and the cell dies. If desired, pH-sensitivity and two-photon processes could be used to further increase the selectivity in addressing very specific regions of the body, such as a tumor.

Photochromic molecules, or photochromes, can be reversibly isomerized between two thermally stable forms by exposure to light of different wavelengths. Upon isomerization, properties such as excitation energies, redox properties, charge distribution, and structure experience significant changes. These changes can be harnessed to switch “on” or “off” the action of a variety of photophysical processes in the photochromic constructs, e.g., energy and electron transfer. Until now, the focus of my research has been to show proof of principle for a large selection of molecule-based photonically controlled logic devices (solution based) with the functional basis in the switching of the transfer processes mentioned above. Now, I wish to extend the study to include experiments in the solid state, e.g., polymer matrices. Taking the step into doing solid state chemistry is not only a prerequisite for any real-world application. It will also allow for experiments that cannot be performed in fluid solution, such as aligning molecules in a stretched film for chemistry with polarized light, and immobilization of molecules for selective addressing in a three-dimensional array of volume elements. Furthermore, I intend to investigate the possibility to photonically control the membrane penetrating and the DNA-binding abilities of photochromes, aiming at, in a long-term perspective, light-activated cancer drugs. Due to the fact that both the structure and the charge distribution of a photochrome may change drastically upon isomerization, one of the two isomeric forms is often suitable for penetrating a membrane. Inside the membrane, e.g., in a cell, the photochrome can be photo-isomerized to a structure with high affinity for strong binding to DNA. Upon binding, transcription is inhibited and the cell dies. If desired, pH-sensitivity and two-photon processes could be used to further increase the selectivity in addressing very specific regions of the body, such as a tumor.

Max ERC Funding

1 000 000 €

Duration

Start date: 2008-09-01, End date: 2013-08-31

Project acronymQPQV

ProjectQuantum plasmas and the quantum vacuum: New vistas in physics

Researcher (PI)Mattias Marklund

Host Institution (HI)UMEA UNIVERSITET

Call DetailsStarting Grant (StG), PE2, ERC-2007-StG

SummaryThe quantum vacuum constitutes a highly nontrivial medium, in which complex nonlinear processes, such as pair production and photon splitting, can take place. These processes will yield measurable alterations to classical electromagnetic wave dynamics and laser-matter interactions using the next-generation laser systems. It has been suggested that this could even give rise to self-compression of electromagnetic pulses in vacuum, and therefore produce intensities above the laser limit. This gives the possibility of anti-matter production, light splitting, and light collisions, that could be of importance for testing the invariance properties of the laws of physics. Furthermore, the properties of the quantum vacuum holds the key to a fundamental understanding of highly magnetized stars, the relation of spacetime dynamics to thermodynamics, and could be used to obtain information about e.g. dark matter candidates. Thus, the effects of the quantum vacuum will be noticeable both on a practical level, in future high intensity field experiments and applications, as well as at the level of basic research, providing crucial information about the properties of the laws of physics. The aim of this proposal is manifold. Using high intensity electromagnetic field generation different aspects of the quantum vacuum will be probed. The experimental investigation of the Unruh effect will yield insight into black hole physics and effects of spacetime structure on quantum field theory. The possibility to detect elastic scattering among photons would open up a completely new branch in science and deepen our understanding of the laws of physics. Moreover, using state-of-the-art laser facilities, methods for probing extreme plasmas, where quantum particle dynamics and the nonlinear quantum vacuum are important, will be developed. This holds promising applications as lasers approach entirely new intensity level in the near future.

The quantum vacuum constitutes a highly nontrivial medium, in which complex nonlinear processes, such as pair production and photon splitting, can take place. These processes will yield measurable alterations to classical electromagnetic wave dynamics and laser-matter interactions using the next-generation laser systems. It has been suggested that this could even give rise to self-compression of electromagnetic pulses in vacuum, and therefore produce intensities above the laser limit. This gives the possibility of anti-matter production, light splitting, and light collisions, that could be of importance for testing the invariance properties of the laws of physics. Furthermore, the properties of the quantum vacuum holds the key to a fundamental understanding of highly magnetized stars, the relation of spacetime dynamics to thermodynamics, and could be used to obtain information about e.g. dark matter candidates. Thus, the effects of the quantum vacuum will be noticeable both on a practical level, in future high intensity field experiments and applications, as well as at the level of basic research, providing crucial information about the properties of the laws of physics. The aim of this proposal is manifold. Using high intensity electromagnetic field generation different aspects of the quantum vacuum will be probed. The experimental investigation of the Unruh effect will yield insight into black hole physics and effects of spacetime structure on quantum field theory. The possibility to detect elastic scattering among photons would open up a completely new branch in science and deepen our understanding of the laws of physics. Moreover, using state-of-the-art laser facilities, methods for probing extreme plasmas, where quantum particle dynamics and the nonlinear quantum vacuum are important, will be developed. This holds promising applications as lasers approach entirely new intensity level in the near future.

Max ERC Funding

1 000 000 €

Duration

Start date: 2008-08-01, End date: 2013-07-31

Project acronymTF DYNAMICS IN VIVO

ProjectTranscription Factor Dynamics in Living Cells at the Single Molecule Level

Researcher (PI)Johan Elf

Host Institution (HI)UPPSALA UNIVERSITET

Call DetailsStarting Grant (StG), LS2, ERC-2007-StG

SummaryProgress in bioengineering and biomedicine is limited by our inadequate understanding of genetic control systems in living cells. The lack of methods for studying kinetics and gene regulation in single cells seriously impairs our prospects to gain deeper insight to develop better quantitative models of such control systems. This project is focused on transcription factors (TFs), proteins that mediate gene regulation in all kingdoms of life. It aims at understanding how bacterial TFs coordinate the expression of genes at the level of single cells. The experimental challenge of studying TF mediated gene regulation directly is that it is a single molecule process where one or a few TF molecules bind one or a few binding sites on the bacterial chromosome. In addition studying TF kinetics poses two major theoretical challenges: its non-negligible spatial aspects and the stochastic nature of kinetics at the single molecule level. This proposal describes new state-of-the-art single molecule microscopy methods for studying kinetics and diffusion of TFs in living cells. The proposed experimental techniques will be accompanied by pioneering computational methods for stochastic reaction-diffusion modeling of intracellular kinetics. Only by the concomitant advancement of both methodologies will we gain understanding of how transcription factors operate in living cells, how their copy number is maintained, how different classes of TFs optimize their search for chromosomal targets, and how the location of TF genes and binding sites constrain genome evolution. Direct observation of TF dynamics will allow probing gene regulation with unprecedented time resolution. This makes it possible to test hypotheses about coordinated gene regulation which have so far been experimentally inaccessible. The unique combination of single molecule in vivo microscopy and spatially resolved stochastic modeling will advance Europe’s position at the frontier of systems biology.

Progress in bioengineering and biomedicine is limited by our inadequate understanding of genetic control systems in living cells. The lack of methods for studying kinetics and gene regulation in single cells seriously impairs our prospects to gain deeper insight to develop better quantitative models of such control systems. This project is focused on transcription factors (TFs), proteins that mediate gene regulation in all kingdoms of life. It aims at understanding how bacterial TFs coordinate the expression of genes at the level of single cells. The experimental challenge of studying TF mediated gene regulation directly is that it is a single molecule process where one or a few TF molecules bind one or a few binding sites on the bacterial chromosome. In addition studying TF kinetics poses two major theoretical challenges: its non-negligible spatial aspects and the stochastic nature of kinetics at the single molecule level. This proposal describes new state-of-the-art single molecule microscopy methods for studying kinetics and diffusion of TFs in living cells. The proposed experimental techniques will be accompanied by pioneering computational methods for stochastic reaction-diffusion modeling of intracellular kinetics. Only by the concomitant advancement of both methodologies will we gain understanding of how transcription factors operate in living cells, how their copy number is maintained, how different classes of TFs optimize their search for chromosomal targets, and how the location of TF genes and binding sites constrain genome evolution. Direct observation of TF dynamics will allow probing gene regulation with unprecedented time resolution. This makes it possible to test hypotheses about coordinated gene regulation which have so far been experimentally inaccessible. The unique combination of single molecule in vivo microscopy and spatially resolved stochastic modeling will advance Europe’s position at the frontier of systems biology.